This proposal is a competitive renewal of R01-MH-39216. Various studies indicate that symptomatic and, in some cases, remitted depressed patients differ from normals in one or more of the following: REM latency, DST status, subjective and neuroendocrine response to cholinergic agonists, RBC choline, and fibroblast muscarinic receptor counts. These data support the notion that CNS cholinergic systems are hypersensitive in some depressions. Three experiments will evaluate this hypothesized CNS cholinergic hypersensitivity. Different individuals will be used in each experiment. Five subject groups will be studied: (1) symptomatic, unipolar, endogenous, major depressions (ED) with short REM latencies (RLs) (n=20); (2) symptomatic, unipolar, nonendogenous (NED) major depressions with normal RLs (n=20); (3) remitted (ED) depressions (n=10); (4) remitted (NED) depressions (n=10); and (5) normal controls without a personal or family history of depression (n=20). The remitted depressed will be gathered from the symptomatic groups (1) and (2) following clinical remission on all three experiments. Experiment 1 will determine whether these groups differ in the cholinergic REM induction test and will evaluate test-retest reliability. Experiment 2 will determine whether these groups differ in their behavioral and neuroendocrine responses to 2.5 mg/70 mg i.v. arecoline (Cholinergic Stimulation Test) and determine test-retest reliability. Experiment 3 will assess changes in regional cerebral blood flow (rCBF) in response to 4.0 mg/70 mg i.v. arecoline and will evaluate test-retest reliability. Results should identify which depressions evidence CNS cholinergic hypersensitivity; (2) determine which of these three tests is more specific, sensitive, and reliable; (3) determine whether the remitted depressed continue to display these abnormalities; and (4) identify the cortical/subcortical structures that might contribute to the abnormality.